Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1

Purpose: Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogenous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomaldominant pedigree to identify disease loci for keratoconus. Methods: A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at Ϸ10 cM density. This was followed by fine mapping at Ϸ2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2. Results: Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance ϭ 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99 -119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8

Inhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension

YesHeterozygous loss of function mutations in the type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlie the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effect of currently utilized therapies on the TGF-β pathway is not known. Prostacyclin analogues remain the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analogue selectively inhibits proliferation in a dose-dependent manner in mouse primary pulmonary arterial smooth muscle cells (PASMCs) harbouring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. This study demonstrates that this agent inhibits TGF-β1–induced SMAD-dependent and -independent signaling via a PKA dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38MAPK proteins. Finally, in a monocrotaline (MCT)-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil (TPS), a stable prostacyclin analogue, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogues inhibit dysregulated TGF-β signaling in vitro and in vivo and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.The authors acknowledge financial support from the British Heart Foundation, United Kingdom (Programme Grant 1-2004-357 to R.C.T. and N.W.M.), a Heptagon Life Science Proof of Concept Fund (grants KCL24 and KCL25 to M.T.N. and R.C.T., respectively), and the Great Britain Sasakawa Foundation (grant B70 to M.T.N.

Cross-Platform Comparison of Microarray-Based Multiple-Class Prediction

High-throughput microarray technology has been widely applied in biological and medical decision-making research during the past decade. However, the diversity of platforms has made it a challenge to re-use and/or integrate datasets generated in different experiments or labs for constructing array-based diagnostic models. Using large toxicogenomics datasets generated using both Affymetrix and Agilent microarray platforms, we carried out a benchmark evaluation of cross-platform consistency in multiple-class prediction using three widely-used machine learning algorithms. After an initial assessment of model performance on different platforms, we evaluated whether predictive signature features selected in one platform could be directly used to train a model in the other platform and whether predictive models trained using data from one platform could predict datasets profiled using the other platform with comparable performance. Our results established that it is possible to successfully apply multiple-class prediction models across different commercial microarray platforms, offering a number of important benefits such as accelerating the possible translation of biomarkers identified with microarrays to clinically-validated assays. However, this investigation focuses on a technical platform comparison and is actually only the beginning of exploring cross-platform consistency. Further studies are needed to confirm the feasibility of microarray-based cross-platform prediction, especially using independent datasets

Effects of maternal and paternal smoking on attentional control in children with and without ADHD

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3′ untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains

[Comparison of the performance of three prehospital trauma scores in evaluation of injury severity among Lushan earthquake victims].

OBJECTIVE: To investigate the performance of revised trauma score (RTS), CRAMS score (circulation, respiration, abdomen, motor and speech) and prehospital index (PHI) on evaluation of injury severity in earthquake victims. METHODS: Data of victims admitted to West China Hospital of Sichuan University during the Lushan earthquake from April 20th, 2013, to April 27th were retrospectively analyzed. The clinical information at admission was recorded, and the injury severity score (ISS), RTS, CRAMS and PHI were calculated. The optimal cut-off values were looked for, the comparability between the three scores and ISS score were figured out by receiver operator characteristic curve (ROC curve), and the correlation between ISS and three scores was analyzed by linear regression analysis. RESULTS: There was a total of 263 victims included in the study. ISS ≥ 16 was found in 86 cases, and ISSvictims, and there were significant statistic differences in male ratio (67.4% vs. 50.8%, χ² = 6.477, P=0.011), RTS score [7.55 (0.29) vs. 7.84 (0), U=6 825, P=0.013] and CRAMS scores [8 (1) vs. 9 (1), U=3 977, P=0.000] between two groups. It was showed by ROC curve analysis that the area under the ROC curve (AUC) of RTS, CRAMS and PHI was 0.547 (P=0.220), 0.734 (P=0.000) and 0.544 (P=0.250), and the Youden indexes of the three scores were 0.093, 0.443, and 0.119, respectively. Moreover, the best cut-off values of them were 4.9, 9.5 and 3.5. Linear regression analysis showed that RTS and CRAMS score showed negative correlation with ISS score (r₁=-0.139, P₁=0.024; r₂=-0.413, P₂=0.000), while PHI showed no relationship with it (r=0.071, P=0.250). CONCLUSIONS: Of these three scoring systems, CRAMS has the best correlation with ISS, and it can be used in the prompt assessment of trauma severity in earthquake victims

Predictors of good outcome s and mortality after thrombectomy for basilar artery occlusion within 12 hours of onset

BACKGROUND: Patients with acute basilar artery occlusion (ABAO) who undergo combined standard medical treatment (SMT) and endovascular thrombectomy (EVT) may still have unsatisfactory outcomes. This study was conducted to identify the factors that may impact their outcomes. METHODS: We retrospectively reviewed the data of all patients with ABAO combined with SMT and EVT in the endovascular treatment for acute basilar artery occlusion (ATTENTION) trial. A good outcome is defined as a modified Rankin Scale (mRS) score of 0-3, a poor outcome as mRS score of 4-6, and mortality as death at 90-day follow-up. The study analyzed various factors influencing the patients\u27 good outcomes and mortality. RESULTS: The study included 221 patients (148 men and 73 women). Among these patients, 45.7% achieved an mRS score of 0-3, while the overall mortality rate was 37.1% (82/221). A good outcome was significantly associated with younger age (adjusted OR 0.96; 95% CI 0.93 to 0.99; P=0.019), a baseline posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) of 8-10 (adjusted OR 2.34; 95% CI 1.07 to 5.12; P=0.034), and post-procedure pc-ASPECTS of 8-10 (adjusted OR 1.40; 95% CI 1.07 to 1.84; P=0.013). Additionally, time from puncture to reperfusion (adjusted OR 2.02; 95% CI 1.2 to 3.41; P=0.008) and intracranial hemorrhage (adjusted OR 3.59; 95% CI 1.09 to 11.8; P=0.035) were associated with 90-day mortality. CONCLUSIONS: Younger age, baseline pc-ASPECTS of 8-10, and higher post-procedure pc-ASPECTS could effectively predict good outcomes for patients with ABAO undergoing EVT. Additionally, a prolonged time from puncture to reperfusion and intracranial hemorrhage can independently predict mortality. TRIAL REGISTRATION NUMBER: NCT04751708